The reference may be made to Nat. Rev. Drug Discov., 6:943-944, 2007 discloses antibiotic resistance is a major global health care concern due to infections related to the escalating multiple drug resistant (MDR) pathogens.
The reference may be made to N. Engl. J. Med. 360:439-443, 2009 and Nature, 499:394- 396, 2013 disclose MDR strains of methicillin resistant Staphylococcus aureus(MRSA), vancomycin resistant Enterrococci (VRE) and carbapenem-resistant Enterobacteriaceae (CREs) in communities and nosocomial environments are rendering antibiotic therapy more difficult and costly at an unprecedented rate.
The reference may be made to Nat. Rev. Microbiol, 2:95-108, 2004 and Chem. Biol., 19:1503-1513, 2012 disclose the development of resistance is aggravated by irrational use of antibiotics in livestock and healthcare practices that has armed microbes with multitude of novel drug resistance mechanisms. Microbes are among the most successful organisms owning to their rapid regeneration time which allows accumulation of resistance conferring genes through antibiotic stress or through exchange of plasmids with other microbes. Additionally a passive, known contributory life style approach towards resistance development in microbes is biofilm formation. Through a network of chemical signals (quorum sensing agents) biofilms nurture slow growing and heterogeneous microbial populations that differ among themselves phenotypically as well as genetically.
The reference may be made to Nat. Rev. Microbiol., 8:623-633, 2010 discloses biofilms are matrix associated microbial communities adhered to surfaces or floating at air-water inter-phase where, the microbes are embedded in a self-produced exopolymeric substance (EPS). The biofilm matrix mostly comprises of proteins, extra cellular DNA with different extracellular polysaccharides.
The reference may be made to Int. J. Antimicrob. Agents., 35:322-332, 2010 discloses the biofilms play a major role in almost 80% infections, including cystic fibrosis, dental plaques, chronic wounds and implanted medical device infections.
The reference may be made to Trends Microbiol., 9:34-39, 2001 discloses most of the antibiotics target growth related metabolic processes in bacteria however, the heterogeneous population of actively dividing and persister microorganism in biofilms make them recalcitrant infection reservoirs which further contributes to virulence since the exopolymeric matrix and retarded metabolic activity inside biofilm communities leads to increased persistence of biofilms.
The reference may be made to Nature., 436:1171-1175, 2005 discloses the bacteria in biofilms generally tolerate antibiotic treatment, and antibiotics can even produce a trigger for biofilm formation.
The reference may be made to Nature, 415:389-395, 2002 and Nat. Rev. Microbiol., 3:238-250, 2005 describe, Host defense cationic peptides [HDCPs] (12-60 mer) and their mimics with several simultaneous target mechanisms in microbes are commercial candidates that hold potential to circumvent drug resistance MDR pathogens.
The reference may be made to Nat. Rev. Microbiol. 3:238-250, 2005 discloses HDCPs are evolutionary conserved and produced as a component of innate immunity by almost all living organisms as a first line of defense against invading microbes. Owing to global amphipathicity i.e. balance between positive charge at physiological pH and hydrophobicity, HDCPs predominantly exhibit membrane disruptive mode of action although they have also been reported as metabolic inhibitors in microbes.
The reference may be made to J. Appl. Microbiol., 104:1-13, 2008 describe the positive charge on HDCPs helps them to get attracted to negatively charged surface of bacterial cells, facilitating primary interactions. After initial attachment, by virtue of their amphipathic nature HDCPs are able to partition in bacterial membranes leading to transient or irreversible cellular content leakage which ultimately leads to bacterial cell death. Due to a rapid killing ability and simultaneous targeting of multiple organelles it is difficult for bacteria to develop resistance against HDCPs. HDCPs have also been reported to efficiently eradicate slow-growing cells from planktonic and biofilm cultures and thus have been proposed as promising alternative agents in the cure of biofilm associated MDR infections as well.
The reference may be made to Nat. Biotechnol, 17:755-757, 1999 describe the bottlenecks in the application of HDCPs have been their high cost, scalability, protease stability, reduced activity in presence of physiological salts concentrations and poor bioavailability.
The reference may be made to Antimicrob. Agents Chemother. 58: 5136-5145, 2014 and J. Appl. Microbiol, 110:229-238, 2011 and J. Antimicrob. Chemother. 64: 735-740, 2009 and J. Med. Chem. 54:786-5795, 2011 describe mimic HDCPs functions in miniature peptidomimetics has lead to discovery of potent molecules such as brilacidin, cationic steroid antibiotics (CSA), XF-73, and LTX-109 most of which are currently under clinical trials as antibacterial agents.
The reference may be made to Int. J. Biochem. Cell. Biol. 42:39-51, 2010 describes the polyamines (putrescine, spermidine, and spermine) are essential organic polycations that modulate cellular processes like nucleic acid packaging, DNA replication, transcription, and translation.
The reference may be made to Expert Rev. Mol. Med. 22:15:e3, 2013 and Bioorg. Med. Chem., 13:2523-2536 and Antimicrob. Agents Chemother., 50:852-861, 2006 describe the synthetic polyamine conjugates exhibit versatile biological activities, including anticancer, antiparasitic, antiendotoxin, and antibacterial activities.
The reference may be made to J. Appl. Microbiol., 110:229-238, 2011 and Bioorg. Med. Chem., 13:2523-2536, 2005 and Arch. Pharm. Res. 31:698-704, 2008 disclose the role of polyamine conjugation in improving activity for a number of synthetic antibacterial agents, such as ceragenins, acylpolyamines, and caffeoyl polyamines.
The reference may be made to Antimicrob. Agents Chemother., 51:2070-2077, 2007 describe the synergistic effect of exogenous polyamines and various antibiotics.
The reference may be made to Org Biomol Chem., 10:8326-8335, 2012 and Antimicrob Agents Chemother., 58:5435-5447, 2014 describe the ultra short di-peptidomimetics based on polyamine backbone that showed excellent anti methicillin resistant S. aureus(MRSA) activity in vitro against planktonic cells. Further, the designed di-peptidomimetics (Org Biomol Chem., 10:8326-8335, 2012) were found equally or rather better active against methicillin resistant S. aureus as compared to S. aureus. Polyamines were initially thought to be ubiquitous and were expected to be present in mammals as well microbes, However, recently it was shown that S. aureus produces no spermine/spermidine or their precursors; therefore, polyamines and their conjugates act as toxins to S. aureus. [Mol. Microbiol. 82:9-20, 2011]
The reference may be made to Cell Host Microbe, 13:100-107, 2013 discloses Further, the exceptional virulence of MRSA strain USA300 was ascribed to development of resistance genes to spermidine and other polyamines.
Therefore, for polyamine-sensitive MRSA, conjugation of spermine is a robust strategy to overcome this deadly strain.